(1) Field of the Invention
This invention relates to a method for refining 2-(aryl substituted)propionic acid or its salt (hereinafter referred to simply as "substituted propionic acid" which is useful as a medicine or an intermediate for preparing organic chemicals such as medicines. More particularly, the present invention relates to a method for refining to prepare highly pure 2-(aryl substituted)propionic acid in which the refining is attained by hydrogen treatment of halogenated by-products such as the halide of substituted propionic acid that are produced together with substituted propionic acid in the procedure of synthesis.
The present invention can be applied, for example, to the preparation of 2-(p-isobutylphenyl)propionic acid or its salts (hereinafter referred to as "IPA") which is used as a medicine or an intermediate for preparing organic chemicals such as medicines. More particularly, the invention relates to a method for recovering highly pure IPA from the remained filtrate of recrystallization, in which method the refining is carried out by hydrogen treatment of halogenated by-products such as halide of IPA (hereinafter referred to as "halogenated IPA") that remains together with IPA in the filtrate of recrystallization.
(2) Description of the Prior Art
In connection with the method for preparing 2-(aryl substituted)propionic acid, various methods have been hitherto proposed. For example, with regard to 2-(p-isobutylphenyl)propionic acid, there are proposed several methods using a starting material of isobutylacetophenone that is prepared by acetylating isobutylbenzene with acetyl chloride in the presence of aluminum chloride catalyst.
(a) A method utilizing Darzens' reaction causing isobutylacetophenone to react with .alpha.-chloroacetic acid in the presence of a salt of alkali metal hydroxide to form epoxy compound, is disclosed in British Patent No. 1,521,906.
(b) Methods utilizing methylation by reacting it with chloroform in the presence of a phase transfer catalyst such as a tert-ammonium salt, are disclosed in British Patent Nos. 971,700 and 2,055,814.
Furthermore, there are methods which start directly from isobutylbenzene.
(a) A method utilizing the reaction with an acyl halide in the presence of aluminum chloride catalyst is disclosed in British Patent No. 971,700.
(b) Methods utilizing chloromethylation with formaldehyde in the presence of hydrochloric acid, or utilizing Grignard reaction to halogenated isobutylbenzene that is obtained by direct halogenation are disclosed in U.S. Pat. Nos. 3,959,364 and 4,433,160 and British Patent No. 2,065,656.
(c) Methods utilizing alkylation reaction in which a halide is reacted in the presence of a metal chloride catalyst such as aluminum chloride are disclosed in U.S. Pat. No. 4,031,215 and Canadian Patent No. 1,077,960.
Furthermore, with regard to 2-(m-benzoylphenyl)propionic acid, a preparation method is disclosed in Japanese Laid-Open Patent Publication No. 55-4311. Still further, another method for preparing 2-(aryl substituted)propionic acid is disclosed in U.S. Pat. No. 4,329,507.
However, in these conventional methods in which several procedures are combined, halogenated compounds which are liable to cause side reaction, are used as raw materials in synthesizing step, or halogenated compounds such as aluminum chloride are used as catalysts. In these reactions, dehalogenation is liable to occur during reaction and reaction agents have a tendency to release free halogen molecules or halogen ions. Thus, various side reaction occurs by the free halogen molecules or halogen ions, which leads the halogenation of starting materials, intermediates during synthesizing process and aimed reaction products. Even though the quantities of halogen compounds are small, the generation of halogenated by-product which is undesirable for the use of the aimed product cannot be avoided. Furthermore, the contamination with halogenated by-product, even when the quantity is very small, is not desirable for the substituted propionic acid which is used in the fields such as medicine in which high purity and high safety are required.
In the refining operation to eliminate impurities, recrystallization is generally adopted, because it cannot generally be attained by distillation. When the contamination with impurities like halogenated by-products must be severely avoided by recrystallization, relatively large quantity of substituted propionic acid is caused to remain in filtrate, which fact inevitably reduces the yield of crystalline substituted propionic acid. Furthermore, in order to eliminate halogenated by-products severely, intricate treatment such as increased number of repetition of recrystallization is also required.
It is difficult to define the chemical structures of the halogenated by-products contained in the 2-(aryl substituted)propionic acid because its quantity is quite small and, for example, as to beforesaid halogenated IPA, there are many isomers of halogenated IPA. Accordingly, the refining of 2-(aryl substituted)propionic acid by chemical method has never been proposed yet.